Periferal arterial disease PAD, also known as peripheral vascular disease (PVD) or peripheral arterial occlusive disease (PAOD) refers to the obstruction of large arteries not within the coronary, aortic arch vasculature, or brain. PAD can result from atherosclerosis, inflammatory processes leading to stenosis, an embolism, or thrombus formation. It causes either acute or chronic ischemia (lack of blood supply). PAD is a form of atherosclerotic disease that affects the peripheral arteries. It commonly manifests in the blood vessels of the legs as claudication, an intermittent pain that occurs with exercise and/or at rest. PAD is prevalent in smokers and diabetics; its incidence increases with age. PAD affects ˜10 million individuals in the US alone. Management of PAD overlaps with coronary disease risk modification, but approved medical therapies for PAD affect platelet viscosity to improve blood flow to peripheral muscles and do not modify disease. PAD shares pathologic features with coronary atherosclerosis, such a chronic vascular inflammation. Interleukins (ILs) are key mediators in the chronic vascular inflammatory response. IL-1β activates endothelial cells, leading to the upregulation of adhesion molecules that promote inflammatory cell adhesion to the vessel wall. IL-1β also increases extracellular matrix and collagen deposition, thereby contributing to plaque burden and arterial wall thickening. Antagonism of IL-1β is an attractive target to ameliorating vessel wall inflammation associated with atherosclerosis.
Inhibition of IL-1 activity is being currently explored for a number of cardiovascular indications via different mechanisms. Anakinra (Kineret) is a human interleukin-1 receptor antagonist that requires daily subcutaneous dosing of approximately 100 mg for efficacy. The MRC-ILA-HEART study is a clinical trial investigating the effects of anakinra upon markers of inflammation in patients with non-ST elevation myocardial infarction (NSTEMI) (Crossman, et al., 2008).
ACZ885 (canakinumab) is a high-affinity, fully human monoclonal antibody to interleukin-1β, developed originally for the treatment of IL-1β-driven inflammatory diseases. Canakinumab has been approved under the trade name ILARIS® in the US for patients ≥4 year of age with Cryopyrin-Associated Periodic Syndromes (CAPS), [Familial Cold-Associated Syndrome (FCAS) and Muckle-Wells syndrome (MWS) phenotypes included. Canakinumab has also received regulatory approvals for treatment of SJIA and gout.